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Berlin Brandenburg

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  • 1
    In: Neuro-Oncology, 2015, Vol. 17(suppl3), pp.iii33-iii33
    Description: Brain tumors are the leading cause of cancer-related mortality in childhood. Based on the many recent genomic studies, we know now that multiple molecular subtypes of brain cancers exist that are not only biologically but also clinically highly distinct. These findings may lead to novel treatment strategies. For this we need better preclinical models that correctly reflect the proper tumor (sub)type. Orthotopic patient-derived xenograft (PDX) models generated by intracranial injection of primary patient material into the brain of NOD scid gamma (NSG) mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Prior to drug selection and testing, extensive molecular characterizations are needed to learn about targetable oncogenic drivers in each model. Therefore, we aim to generate a large repertoire of PDX models reflecting the many different molecular subtypes of pediatric brain cancer. For each established PDX model, we perform DNA methylation profiling, gene expression profiling, low-coverage whole genome sequencing and whole exome sequencing and compare these data with the matching primary tumor. Thus far, as a collaborative effort between different laboratories, we have established and fully characterized 34 PDX models from 1 atypical teratoid rhabdoid tumor (ATRT), 4 ependymoma, 9 glioblastoma, 18 medulloblastoma, and 2 primitive neuroectodermal tumors (PNET). Molecular analysis of all available PDX models identified a clear overrepresentation of most aggressive tumors such as models characterized by MYC- or MYCN amplification. Other, less aggressive cancers, like Wnt medulloblastoma, are underrepresented. For in vivo imaging during treatment of PDX models we created luciferase labeled PDX sublines. Our data demonstrate that PDX models retain characteristics of the primary human tumors from which they were derived. These reagents provide an unprecedented resource to study tumor biology and pave the way for improving treatment strategies of malignant pediatric brain tumors.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
  • 3
    Language: English
    In: Nature medicine, November 2018, Vol.24(11), pp.1752-1761
    Description: Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children's Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and seven cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.
    Keywords: Biological Specimen Banks ; Immunohistochemistry ; Brain Neoplasms -- Pathology ; Xenograft Model Antitumor Assays -- Methods
    ISSN: 10788956
    E-ISSN: 1546-170X
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  • 4
    Language: English
    In: Cancer research, 15 November 2013, Vol.73(22), pp.6828-37
    Description: While medulloblastoma, a pediatric tumor of the cerebellum, is characterized by aberrations in developmental pathways, the majority of genetic determinants remain unknown. An unbiased Sleeping Beauty transposon screen revealed MyoD as a putative medulloblastoma tumor suppressor. This was unexpected, as MyoD is a muscle differentiation factor and not previously known to be expressed in cerebellum or medulloblastoma. In response to deletion of one allele of MyoD, two other Sonic hedgehog-driven mouse medulloblastoma models showed accelerated tumor formation and death, confirming MyoD as a tumor suppressor in these models. In normal cerebellum, MyoD was expressed in the proliferating granule neuron progenitors that are thought to be precursors to medulloblastoma. Similar to some other tumor suppressors that are induced in cancer, MyoD was expressed in proliferating medulloblastoma cells in three mouse models and in human medulloblastoma cases. This suggests that although expression of MyoD in a proliferating tumor is insufficient to prevent tumor progression, its expression in the cerebellum hinders medulloblastoma genesis.
    Keywords: Cerebellar Neoplasms -- Genetics ; Genes, Tumor Suppressor -- Physiology ; Medulloblastoma -- Genetics ; Myod Protein -- Physiology
    ISSN: 00085472
    E-ISSN: 1538-7445
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  • 5
  • 6
    Language: English
    In: Virus Research, May 2019, Vol.265, pp.115-121
    Description: HIV-1 spreads through both the release of cell-free particles and by cell-to-cell transmission. Mounting evidence indicates that cell-to-cell transmission is more efficient than cell-free transmission of particles and likely influences the pathogenesis of HIV-1 infection. This mode of viral transmission also influences the generation and maintenance of the latent reservoir, which represents the main obstacle for curing the infection. In this review we will discuss general cell contact-dependent mechanisms that HIV-1 utilizes for its spread and the evidence pointing to cell-to-cell transmission as a mechanism for the establishment and maintenance of latent infection.
    Keywords: HIV Cell-to-Cell Transmission ; HIV Latency ; Virological Synapse ; Infectious Synapse ; Dendritic Cells ; Cd4 T Cells ; Resting Cd4 T Cells ; Biology
    ISSN: 0168-1702
    E-ISSN: 1872-7492
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  • 7
    Language: English
    In: Science translational medicine, 22 April 2015, Vol.7(284), pp.284ra58
    Description: A fundamental problem in cancer drug development is that antitumor efficacy in preclinical cancer models does not translate faithfully to patient outcomes. Much of early cancer drug discovery is performed under in vitro conditions in cell-based models that poorly represent actual malignancies. To address this inconsistency, we have developed a technology platform called CIVO, which enables simultaneous assessment of up to eight drugs or drug combinations within a single solid tumor in vivo. The platform is currently designed for use in animal models of cancer and patients with superficial tumors but can be modified for investigation of deeper-seated malignancies. In xenograft lymphoma models, CIVO microinjection of well-characterized anticancer agents (vincristine, doxorubicin, mafosfamide, and prednisolone) induced spatially defined cellular changes around sites of drug exposure, specific to the known mechanisms of action of each drug. The observed localized responses predicted responses to systemically delivered drugs in animals. In pair-matched lymphoma models, CIVO correctly demonstrated tumor resistance to doxorubicin and vincristine and an unexpected enhanced sensitivity to mafosfamide in multidrug-resistant lymphomas compared with chemotherapy-naïve lymphomas. A CIVO-enabled in vivo screen of 97 approved oncology agents revealed a novel mTOR (mammalian target of rapamycin) pathway inhibitor that exhibits significantly increased tumor-killing activity in the drug-resistant setting compared with chemotherapy-naïve tumors. Finally, feasibility studies to assess the use of CIVO in human and canine patients demonstrated that microinjection of drugs is toxicity-sparing while inducing robust, easily tracked, drug-specific responses in autochthonous tumors, setting the stage for further application of this technology in clinical trials.
    Keywords: Antineoplastic Agents -- Chemistry ; Drug Screening Assays, Antitumor -- Methods ; Lymphoma -- Drug Therapy ; Neoplasms -- Drug Therapy
    ISSN: 19466234
    E-ISSN: 1946-6242
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  • 8
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(6), p.e0130832
    Description: Anthrax toxin receptors act as molecular clamps or switches that control anthrax toxin entry, pH-dependent pore formation, and translocation of enzymatic moieties across the endosomal membranes. We previously reported that reduction of the disulfide bonds in the immunoglobulin-like (Ig) domain of the anthrax toxin receptor 2 (ANTXR2) inhibited the function of the protective antigen (PA) pore. In the present study, the disulfide linkage in the Ig domain was identified as Cys255-Cys279 and Cys230-Cys315. Specific disulfide bond deletion mutants were achieved by replacing Cys residues with Ala residues. Deletion of the disulfide bond C255-C279, but not C230-C315, inhibited the PA pore-induced release of the fluorescence dyes from the liposomes, suggesting that C255-C279 is essential for PA pore function. Furthermore, we found that deletion of C255-C279 did not affect PA prepore-to-pore conversion, but inhibited PA pore membrane insertion by trapping the PA membrane-inserting loops in proteinaceous hydrophobic pockets. Fluorescence spectra of Trp59, a residue adjacent to the PA-binding motif in von Willebrand factor A (VWA) domain of ANTXR2, showed that deletion of C255-C279 resulted in a significant conformational change on the receptor ectodomain. The disulfide deletion-induced conformational change on the VWA domain was further confirmed by single-particle 3D reconstruction of the negatively stained PA-receptor heptameric complexes. Together, the biochemical and structural data obtained in this study provides a mechanistic insight into the role of the receptor disulfide bond C255-C279 in anthrax toxin action. Manipulation of the redox states of the receptor, specifically targeting to C255-C279, may become a novel strategy to treat anthrax.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 9
    In: Nature, 2015, Vol.518(7538), p.254
    Description: The alternative non-homologous end-joining (NHEJ) machinery facilitates several genomic rearrangements, some of which can lead to cellular transformation. This error-prone repair pathway is triggered upon telomere de-protection to promote the formation of deleterious chromosome end-to-end fusions. Using next-generation sequencing technology, here we show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres. Investigating the enzymatic activity responsible for the random insertions enabled us to identify polymerase theta (Polθ; encoded by Polq in mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq in mice results in increased rates of homology-directed repair, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we show that depletion of Polθ has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 10
    Language: English
    In: Nature, Feb 12, 2015, Vol.518(7538), p.254(16)
    Description: The alternative non-homologous end-joining (NHEJ) machinery facilitates several genomic rearrangements, some of which can lead to cellular transformation. This error-prone repair pathway is triggered upon telomere de-protection to promote the formation of deleterious chromosome end-to-end fusions (1-3). Using next-generation sequencing technology, here we show that repair by alternative NHEJ yields non-TTAGGG nucleotide insertions at fusion breakpoints of dysfunctional telomeres. Investigating the enzymatic activity responsible for the random insertions enabled us to identify polymerase theta (Pol[theta]; encoded by Polq in mice) as a crucial alternative NHEJ factor in mammalian cells. Polq inhibition suppresses alternative NHEJ at dysfunctional telomeres, and hinders chromosomal translocations at non-telomeric loci. In addition, we found that loss of Polq in mice results in increased rates of homology-directed repair, evident by recombination of dysfunctional telomeres and accumulation of RAD51 at double-stranded breaks. Lastly, we show that depletion of Pol[theta] has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair genes.
    Keywords: DNA Polymerases – Physiological Aspects ; Genetic Recombination – Research
    ISSN: 0028-0836
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